RIP3 deficiency attenuated hepatic stellate cell activation and liver fibrosis in schistosomiasis through JNK-cJUN/Egr1 downregulation

Song, Lijun; Yin, Xin; Guan, Shengwen; Gao, Hong; Dong, Panpan; Mei, Congjin; Yang, Yingying; Zhang, Ying; Yu, Chuan-xin; Hua, Zichun

doi:10.1038/s41392-022-01019-6

Cited by 7 publications

(5 citation statements)

References 5 publications

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“…Hepatocellular carcinoma and chronic inflammation are influenced by the RIPK1-related inflammatory response [ 114 ]. RIPK3 deficiency was shown to attenuate hepatic stellate cell activation and liver fibrosis in schistosomiasis through the downregulation of the JNK-cJUN/Egr1 axis [ 115 ]. Furthermore, in a study of necroptosis in renal ischemia–reperfusion injury, it was shown that Nec-1 attenuates cisplatin-induced acute kidney injury [ 116 ].…”

Section: The Mechanisms Of Necroptosismentioning

confidence: 99%

The double-edged functions of necroptosis

Chen

2023

Cell Death Dis

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Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a “double-edged sword” in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death.

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Section: The Mechanisms Of Necroptosismentioning

confidence: 99%

The double-edged functions of necroptosis

Chen

2023

Cell Death Dis

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“…Song and colleagues showed that RIP3 was highly expressed in hepatocytes and CD45 + cells in hepatic fibrosis induced by schistosome infection. RIP3 regulates inflammation and ROS production through the c-Jun N-Terminal Kinase (JNK)-pJUN/Early growth response factor 1 (Egr1) signaling pathway, and knockdown of RIP3 reduces inflammation and hepatic fibrosis caused by schistosome infection [ 77 ]. This finding suggests a role of RIP3-mediated necroptosis in the promotion of hepatic fibrosis during schistosomiasis.…”

Section: The Role Of Programmed Cell Death In Hepatic Fibrosismentioning

confidence: 99%

Programmed cell death in hepatic fibrosis: current and perspectives

Lu,

Yu,

Song

2023

Cell Death Discov.

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The initiation, development and resolution of hepatic fibrosis are influenced by various cytokines, chemokines, damage-associated molecular patterns (DAMPs) and signaling pathways. A significant number of studies in recent years have indicated that the progression of hepatic fibrosis is closely linked to programmed cell death processes such as apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, cuproptosis, and PANoptosis. Inducement of hepatic stellate cells (HSCs) death or preventing death in other liver cells can delay or even reverse hepatic fibrosis. Nevertheless, the roles of programmed cell death in hepatic fibrosis have not been reviewed. Therefore, this review summarizes the characteristics of various of hepatic fibrosis and programmed cell death, focuses on the latest progress of programmed cell death in the promotion and regression of hepatic fibrosis, and highlights the different roles of the programmed cell death of HSCs and other liver cells in hepatic fibrosis. In the end, the possible therapeutic approaches targeting programmed cell death for treating hepatic fibrosis are discussed and prospected.

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“…Studies have shown that markers of necroptosis (RIPK3, MLKL, and phospho-MLKL) are increased in the livers of MAFLD and MASH patients, and in mouse models of MASH [ 10 , 11 , 12 , 13 , 14 , 15 ]. Consequently, inhibiting necroptosis, either through pharmacological targeting of RIPK1 or genetic/pharmacological targeting of RIPK3, has been demonstrated to decrease liver inflammation and fibrosis in mouse models of MAFLD [ 12 , 16 , 17 ]. We have previously shown that the inhibition of necroptosis using necrostatin-1s, a pharmacological inhibitor of RIPK1, reduced liver inflammation and fibrosis in mouse models of spontaneous MASH, i.e., old wild-type mice and Sod1 −/− mice [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model

Ohene-Marfo,

Nguyen,

Mohammed

et al. 2024

IJMS

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Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to the diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain-like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD. Despite the HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl−/− mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+/− mice showed a significant reduction in these parameters that was associated with elevated Pparα and Pparγ levels. Both Mlkl−/− and Mlkl+/− mice on the HFHFrHC diet resisted diet-induced obesity, attributed to the increased beiging, enhanced oxygen consumption, and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue-specific effects of MLKL on the liver and adipose tissue, and they suggest a dose-dependent effect of MLKL on liver pathology.

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RIP3 deficiency attenuated hepatic stellate cell activation and liver fibrosis in schistosomiasis through JNK-cJUN/Egr1 downregulation

Cited by 7 publications

References 5 publications

The double-edged functions of necroptosis

The double-edged functions of necroptosis

Programmed cell death in hepatic fibrosis: current and perspectives

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model

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